Acquired immune deficiency syndrome (AIDS) is characterized by a severe deficiency in the helper T cells of the immune system. Human immunodeficiency virus (HIV), which causes AIDS, is a member the lentiviruses that are part of a large group of viruses known as the Retroviridae. Retroviridae also include closely related simian, feline, and bovine immunodeficiency viruses that share a variety of common features.
The fact that HIV has a tendency to mutate to forms that are resistant to existing antiviral therapies greatly complicates attempts to treat the infection with antiviral drugs. Most of the current research in AIDS is aimed at understanding the life cycle of HIV to develop treatments targeted to inhibit the virus at different stages of its life cycle.
The normal flow of genetic information is from DNA to RNA to protein. However, HIV virions carry RNA into their host cell and must first convert their viral genomic RNA into a double-stranded DNA in order to start their replication cycle in the host cell. This conversion is directed in the host cell cytoplasm by a viral enzyme called reverse transcriptase (RT). Thus, RT is an attractive target for HIV inhibitors.
HIV RT inhibitors can be broadly classified into nucleoside and non-nucleoside RT inhibitors. The modes of action of these two classes of compounds are different in nature. The nucleoside HIV RT inhibitors are competitive inhibitors that bind to the catalytic site of the enzyme, and their mode of action appears to be through their triphosphates (produced in the cytoplasm of the host cell) that act as RT enzyme inhibitors through incorporation and termination of the growing viral DNA chain. Common nucleoside RT inhibitors (NRTIs) include AZT, ddC, ddI, d4T, 3TC, and Abacavir. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are non-competitive inhibitors of the RT enzyme; they bind to an allosteric (regulatory) site and influence the RT catalytic site. Hence, they are also referred to as second-site RT inhibitors. In general, at micromolar concentrations NNRTIs inhibit HIV-1 in vitro with minimum or no cytotoxicity but do not inhibit HIV-2 or other retroviruses. NNRTIs include chloro-TIBO, nevirapine, L-697,661, and delavirdine.
Sultams (2,3-dihydrobenzo[d]isothiazole 1,1-dioxides) are potent NNRTIs. The enantiomeric form of sultams is important to the potency of HIV-1 RT inhibition. Therefore, efficient synthesis of pure enantiomers of the racemates of active sultam compounds is desirable.
The need and research for active inhibitors of human immunodeficiency virus-1 RT is urgent and ongoing.
The invention relates to the catalytic synthesis of sultams, which are useful as non-nucleoside inhibitors of reverse transcriptase. In sultam synthesis from saccharin, the most crucial step is the asymmetric reduction of the Cxe2x95x90N intermediate, which defines the stereochemistry of the sultam. In accordance with the invention, it is of vital importance to develop a catalyst which would carry out reductions of these imines stereoselectively. Other catalysts of the type have proven to be inefficient for the asymmetric reduction of imines to form sultams, resulting in a low enantiomeric excess (ee). By defination, ee is (excess of one enantiomer over the other enantiomer)/(entire mixture)xc3x97100% and is used to express relative amounts of enantiomers in a mixture.
Publications of interest relating to the subject matter of this invention include:
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Of particular interest are publications on other catalytic systems explored in the field of interest.
Oppolzer, et al., discloses preparation of enantiomerically pure sultams (R)-2 and (S)-2 from non-chiral saccharin. Methyllithium in diethyl ether was added to saccharin to form a prochiral imine which was converted to pure (R)-2 sultam by hydrogenation with the catalyst Ru2Cl4[(R)-(+)-BINAP]2(NEt3) in 72% yield, and was converted to enantiomerically pure (S)-2 sultam using analogous catalyst, (S)-(xe2x88x92)-BINAP in 71% yield.
Noyori and colleagues reported a catalyst system based on ruthenium which was used for a series of carbonyl and imine hydrogen-transfer reductions on some heterocyclic compounds. In these systems, the outcome of the reduction could be predicted. (R)-isomers were generated using an (S,S)-catalyst, and (S)-isomers were generated using an (R,R)-catalyst. Both the preformed catalyst precursor and the true catalyst were reported.
Ahn et al. (1997) J. Org. Chem. 62: 7047-7048 obtained results for some sultams that were directly opposite to those predicted by Noyori""s rule when the Noyori catalysts were used. In Ahn""s system, when the the 3-substituents were alkyl (e.g., Me- or t-Bu) or aryl (e.g., benzyl), the (S,S)-catalyst gave (S)-isomers. Therefore, the approach of the catalyst to the Cxe2x95x90N center comes from opposite directions in the Noyori system from that of the Ahn system.
Stinson (1998) Chem. and Eng. News 76 (22):15-24, reported a rhodium-based catalyst for highly enantioselective reductions of carbonyls and imines.
Mashima et al. (1998) Chem. Letters 1199-1202, reported rhodium and iridium complexes of(1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine which functioned as catalyst precursors for asymmetric transfer hydrogenation. The catalyst had an (S,S) structure, and the reductions carried out were limited to carbonyl group reductions such as the conversion of Cxe2x95x90O to CHxe2x80x94OH.
Most recently, Pfaltz and coworkers report high enantioselectivity when iridium-catalyzed hydrogenation of prochiral imines were performed in supercritical carbon dioxide. The phase behavior of the reaction mixture and the increased solubility of the catalyst in solution were key to the improved selectivity. This new solvent system has the added advantage of being environmentally friendly.
All references referred to in this text are incorporated herein by reference in their entirety.
Catalytic asymmetric reduction of multiple bonds has received much attention in recent years- in particular, asymmetric hydrogenation due, in part, to the importance of optically active amines as pharmaceuticals and agrochemicals. Among the methods available for reductions, asymmetric transfer hydrogenation has advantages over other processes in operational simplicity that avoids the use of gaseous hydrogen. In recent years C2-symmetric diamine-ruthenium(II) complexes have been advanced for overcoming the relatively low reactivities observed for the transfer hydrogenation of imines. Of particular importance is the ability to effect catalytic transfer hydrogenation of the imines stereoselectively since the chirality of the resulting sultam is pivitol to the biological activity of the compound.
The invention provides pre-catalysts and catalysts which are suitable for the efficient synthesis of enantiomerically pure forms of sultams which may be used as HIV RT inhibitors.
The invention also provides a method for preparing enantiomerically pure sultams suitable for use as HIV RT inhibitors.
An objective of the synthesis was to obtain biologically active compounds, especially anti-HIV-1 compounds. The sultam compounds of the invention offer a variety of structural modifications and various possibilities of positioning different substituents in different positions on any one of the rings. It was not known prior to this invention what effect these various substituents and their different positions on the nitrogen, on the stereogenic carbon, and on the ring(s) would have on their biological and, more particularly, their anti-HIV-1 activity.
The invention also provides a new class of such compounds in enantiomerically enriched form which can be purified into their respective enantiomers. A group of these compounds has an anti-HIV potency heretofore unachieved for this class of compounds. In accordance with the invention, an area of the molecule has been identified on which appropriate substituents appear to make a major contribution to a high degree of anti-HIV potency.
The invention also provides a method for treating or preventing viral infections, especially strains of the HIV virus, with the sultams of the invention.
The invention also provides biologically active compositions, which comprise one or more compounds of the invention, in an effective, non-toxic amount in combination with a biologically or pharmaceutically acceptable carrier.
The invention also provides drug combinations of compounds of the invention with HIV protease inhibitors, like ritonavir, saquinavir mesylate, and others.
In still another aspect, the invention provides a method for treating a mammal, particularly a human, infected with a retrovirus, which comprises administering to said mammal an effective nontoxic amount of the composition(s) of the invention.
In summary, the invention contributes to the solution for a serious and urgent world-wide health need which has adverse social and economic consequences.